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Science Overview:
TDP-43

ALS Center at the Penn Neurological InstituteTDP-43 and its role on ALS

Last updated 3/2009

Dana Falcone, MS, CGC

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive deterioration of motor nerve cells (neurons) in the brain and spinal cord. These motor neurons, which initiate and control muscle movement throughout the body, slowly degrade over time until they are no longer functional.

The pathology of the nervous system in ALS is characterized by abnormal accumulation of insoluble and misshaped proteins in degenerating motor neurons. Until recently, very little was known about which specific proteins were included in these accumulations, but it was widely accepted that the proteins were ubiquinated. An ubiquinated protein has been "tagged" by the cell to be destroyed and eliminated. When the removal process fails, the tagged protein can build up and cause disease; in the case of ALS, this occurs in the motor neurons.

Recent advances in research have identified an ubiquinated protein that is commonly found in the majority of ALS cases. In healthy nerve cells this protein, called TDP-43, is typically localized to the nucleus. The nucleus is where the cell stores the information required to make proteins needed for normal cell function. However, in affected nerve cells, TDP-43 is only found in the cytoplasm. The cytoplasm is located outside of the nucleus and is the primary site for chemical activity in the cell. Additionally, biochemical studies have shown that the accumulated TDP-43 located in the affected nerve cells contain abnormal variants of the protein. The accumulation of abnormal TDP-43 in this area of the cell is speculated to cause a loss in cellular function (due to the absence of normal TDP-43 in the nucleus), thereby impairing the viability of the affected nerve cells.

TDP-43 is also a major disease protein in another neurodegenerative condition known as frontotemporal dementia (FTD). FTD is characterized by gradual and progressive changes in behavior and/or language dysfunction. One specific type of FTD is called FTLD-U (Frontotemporal lobar dementia with ubiquitin) and further research on TDP-43 has shown strong evidence that abnormal TDP-43 protein is directly involved in the development of both ALS and FTLD-U. Before the discovery of TDP-43 it was known that approximately 15% of individuals with ALS also have a clinical diagnosis of FTD. Due to the discovery of TDP-43 FTLD-U and ALS are now recognized as representing different manifestations of the same disease process and are considered to belong to a new biochemical class of neurodegenerative disease known as the TDP-43 proteinopathies. Other rare forms of ALS such as that affecting the Chamorro ethnic minority on Guam are also linked to TDP-43 pathology.

There are two notable variations of ALS: familial and sporadic. The majority of patients with ALS are the first person in their family to be diagnosed with the condition; this is known as sporadic ALS. However, a small percentage of individuals with ALS have another close family member with ALS, this is known as familial ALS. Similarities in the clinical course and pathological findings of sporadic ALS and familial ALS have led to the theory that investigating familial forms of ALS will reveal the disease mechanisms behind sporadic ALS. Previously, only one gene, commonly known as SOD1, had been associated with a significant proportion of familial ALS. Consequently, a large portion of ALS research has focused on the properties of SOD1 mutations, and knowledge harvested from these studies has heavily influenced the development of therapeutic medications for ALS.

Studies on the genetics of ALS have shown that about 20% of familial ALS cases are due to SOD1 mutations, but the in the remaining 80% of familial cases a gene or genes had not been identified. Abnormal TDP-43 is not present in cases of ALS with SOD1 mutations, which suggests that SOD1-related ALS and sporadic ALS are not caused by the same disease mechanisms. However, abnormal TDP-43 is present in familial cases of ALS that lack SOD1 mutations, which suggests some familial and sporadic ALS cases are caused by similar mechanisms.

Recently mutations in the gene that codes for the TDP-43 protein (known as TARDBP) have been discovered in individuals with ALS and have been shown to account for approximately 2-6% of all familial ALS cases. The discovery of mutations in the TARDBP gene implies that the accumulation of abnormal TDP-43 protein alone may be sufficient to cause ALS and suggests that TDP-43 could serve as a biomarker for sporadic ALS. The cases of familial ALS associated with TARDBP mutations have been shown to be inherited in an autosomal dominant pattern. In autosomal dominant inheritance, a change in only one gene from a gene pair is necessary in order for an individual to be affected. Each time an individual has a child, there is a 50% chance of passing on the copy of the gene with the change, and a 50% chance of passing on the copy without the change. Families with TARDBP mutations have had different ages of onset and rates of progression both between different families and individuals in the same family suggesting that additional genetic or environmental factors may be involved in the expression of TARDBP mutations.

A recent study has shown that TDP-43 protein can be detected in blood samples and that levels of the protein are elevated in some patients with Alzheimer disease and FTD. Two other small studies in Germany and Japan detected TDP-43 in cerebral spinal fluid (CSF) and found increased levels of TDP-43 in some patients with sporadic ALS. These findings suggest that TDP-43 protein can be detected in bodily fluids such as blood and CSF and may lead to the discovery of a diagnostic test for both ALS and some forms of FTD.

There is still much to learn about TDP-43 and its role in the development of ALS and FTD. Knowledge gained through research will aid us in developing tests to identify the levels of normal and abnormal TDP-43 in the body, and may lead to the identification of new mutations or even new disease genes which would in turn open more avenues of research. Tools like these would allow us to monitor and record the response of patients undergoing disease modifying therapies. In addition, TDP-43 may be used as a target to develop new therapeutic strategies for ALS and FTD.

If you have questions about TDP-43 research or would like to participate in related studies please contact:

Dana Falcone, MS, CGC
Genetic Counselor
Center for Neurodegenerative Disease Research
University of Pennsylvania
Phone: 215-615-3226
Email: cdana@mail.med.upenn.edu
Beth McCarty Wood, MS, CGC
Genetic Counselor
Center for Neurodegenerative Disease Research
University of Pennsylvania
Phone: 215-662-6014
Email: mccarty@mail.med.upenn.edu


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